CD8 positive cytotoxic T lymphocytes (CTLs) have been shown to recognize epitope peptides derived from the tumor-associated antigens (TAAs) found on the major histo-compatibility complex (MHC) class I molecule, and then kill the tumor cells. Since the discovery of the melanoma antigen (MAGE) family as the first example of TAAs, many other TAAs have been discovered, primarily through immunological approaches (NPL 1, 2). Some of these TAAs are currently undergoing clinical development as immunotherapeutic targets.
TAAs which are indispensable for proliferation and survival of cancer cells are valiant as targets for immunotherapy, because the use of such TAAs may minimize the well-described risk of immune escape of cancer cells attributable to deletion, mutation, or down-regulation of TAAs as a consequence of therapeutically driven immune selection. Accordingly, the identification of new TAAs capable of inducing potent and specific anti-tumor immune responses, warrants further development. Thus the clinical application of peptide vaccination strategies for various types of cancer is ongoing (NPL 3-10). To date, there have been several reports of clinical trials using these tumor-associated antigen derived peptides. Unfortunately, so far these cancer vaccine trials have yielded only a low objective response rate has been observed in these cancer vaccine trials so far (NPL 11-13). Accordingly, there remains a need in the art for new TAAs suitable for use as immunotherapeutic targets.
Recently, the present inventors have identified an oncofetal antigen, insulin-like growth factor II mRNA-binding protein 3 (IMP-3), that is frequently overexpressed in lung cancer, head-and-neck cancer (HNC), esophageal cancer and various other malignancies using genome-wide cDNA microarray analysis (NPL 14, PTL 1-3).1 The present inventors have also identified highly immunogenic IMP-3-derived short peptides (SPs) that can induce HLA-A2 (A*02:01)-restricted CTLs and HLA-A24 (A*24:02)-restricted CTLs from peripheral blood mononuclear cells (PBMCs) of lung cancer patients (NPL 14, 15, PTL 2, 3). Therefore, IMP-3 remains an attractive target molecule for cancer immunotherapy. Phase I/II clinical trials of cancer immunotherapy for lung cancer, head and neck cancer (HNC), esophageal cancer, and colorectal cancer using IMP-3-derived CTL-epitopes are underway (NPL 14-18).
Tumor-specific CD4+ helper T (Th) cells, especially T-helper type 1 (Th1) cells play a critical role in efficient induction of CTL-mediated antitumor immunity (NPL 19). The IFN-gamma primarily produced by Th1 cells is critical for induction and maintenance of long lived CTL responses, providing help through multiple interactions which are critical in the preservation of immunological memory (NPL 20, 21). The IFN-gamma secreted by Th1 cells also mediates direct antitumor or anti-angiogenic effect (NPL 22). Furthermore, it has been shown that Th cells must pave the way for entry of CTLs at tumor site (NPL 23). Therefore, identification of tumor-associated antigen (TAA)-derived Th cell epitopes that can activate specific Th1 cell is important for induction of an effective tumor immunity in tumor-bearing hosts; ideally, the design of effective vaccines should include multiple epitopes to stimulate both CTL and Th1 cells (NPL 24). However, no such epitope derived from IMP-3 has yet been identified.